Development and Testing of New Computational Methods for Ligand Discovery and Mechanism

摘要 长期目标是开发配基发现方法，将这些方法应用于活性生物学问题 利息。我们有四个重点：一、开发新的计算对接方法，在简单的 实验模型系统(GM59957支持)。二、这些方法在G蛋白偶联中的应用 受体(GPCRs)，因为它们提供的生物学特性而被广泛研究，以及用于大型- 刻度对接(U19 GM106990)。三、药物中胶体聚集的机理及其影响的研究 发现号。这些小分子胶体，是早期发现的人工制品的最大来源，并影响 整个药物开发流程中的分子(GM71630)。四、鉴于我们的前三个焦点采用了 基于靶点的配体发现观点，我们的第四个领域回到了经典药理学，采用了一种配体- 基于化学信息学的策略，不寻求为已建立的靶标发现新的配体，而是为 已建立的药物和试剂试图预测目标。这个项目已经成为公众的场所 化学信息学、数据库和对接的访问工具(GM71896)。在这里，我们扩展这些项目。我。 开发了新的对接方法，包括处理有序水、共价识别和配体 内部能量紧张。在模型中，通过量热法和结晶学对它们进行了实验测试 洞穴位置。二、与Kobilka和Roth实验室合作，我们为GPCR寻找新的化学类型，包括µ- 阿片受体，M_2和M_3受体，以及β_2-肾上腺素能受体； 变构配体。三、我们深化了对胶体聚集体的物理机制和影响的研究， 关注它们在晚期临床候选人中的持久性，它们的结构和机制，以及 特异性地将胶体药物有效载荷运送到细胞的抗体结合物。四、工具和数据库 发展仍然是一个关键重点。化学信息学的一个新的发展方向是全面和 按序列或按生物信息学相似性组织的目标与相同目标的系统比较 根据它们的配体的相似性进行组织。初步结果表明，靶点对按序列组织，共- 表达或蛋白质-蛋白质相互作用与相似配体相关的配对是正交的。物质基础是 探索过了。

ABSTRACT The long-term goal is to develop ligand discovery methods, applying these to questions of active biological interest. We have four foci: i. development of new computational docking methods, testing these in simple experimental model systems (supported by GM59957). ii. Application of these methods to G Protein Coupled Receptors (GPCRs), which are intensely studied for the biology they confer, and wonderful templates for large- scale docking (U19 GM106990). iii. Investigation of the mechanism and impact of colloidal aggregation in drug discovery. These small molecule colloids, are the greatest source of artifacts in early discovery, and affect molecules throughout the drug development pipeline (GM71630). iv. Whereas our first three foci adopt a target-based view of ligand discovery, our fourth area returns to classical pharmacology, adopting a ligand- based chemoinformatic strategy that seeks not to discover new ligands for established targets, but rather for established drugs and reagents attempts to predict targets. This project has been the venue for the public access tools for chemoinformatics, databases, and docking (GM71896). Here we extend these projects. i. New docking methods are developed, including treating ordered waters, covalent recognition, and ligand internal energy strain. These are tested experimentally—by calorimetry and crystallography—in the model cavity sites. ii. Working with the Kobilka and Roth labs, we seek novel chemotypes for GPCRs including the µ- opioid receptor, the muscarinic M2 and M3 receptors, and the β2-adrenergic receptors; a particular focus are allosteric ligands. iii. We deepen our investigation of the physical mechanism and impact colloidal aggregates, focusing on their persistence among late stage clinical candidates, their structure and mechanism, and antibody conjugates that specifically deliver colloidal drug payloads to cells. iv. Tool and database development remains a key focus. A new direction for the chemoinformatics is a comprehensive and systematic comparison of targets organized by sequence or by bioinformatics similarity, to the same targets organized by the similarity of their ligands. Preliminary results suggest target pairs organized by sequence, co- expression or protein-protein interactions are orthogonal to pairs related by similar ligands. A physical basis is explored.